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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6077-6084. Prepublished online as a Blood First Edition Paper on February 17, 2009; DOI 10.1182/blood-2008-11-187880. This Article Full Text Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2008-11-187880v1 113/24/6077    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Schmiegelow, K. Articles by Weinshilboum, R. PubMed PubMed Citation Articles by Schmiegelow, K. Articles by Weinshilboum, R. Related Collections Free Research Articles Lymphoid Neoplasia Clinical Trials and Observations Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study Kjeld Schmiegelow1,2, Ibrahim Al-Modhwahi2, Mette Klarskov Andersen3, Mikael Behrendtz4, Erik Forestier5, Henrik Hasle6, Mats Heyman7, Jon Kristinsson8, Jacob Nersting2, Randi Nygaard9, Anne Louise Svendsen10, Kim Vettenranta11, Richard Weinshilboum12, for the Nordic Society for Paediatric Haematology and Oncology 1 Faculty of Medicine, Institute of Gynecology, Obstetrics, and Pediatrics, University of Copenhagen, Copenhagen, Denmark; 2 Department of Pediatrics and 3 The Cytogenetic Laboratory, The University Hospital Rigshospitalet, Copenhagen, Denmark; 4 Department of Pediatrics, The University Hospital Linkjöping, Stockholm, Sweden; 5 Department of Pediatrics, The University Hospital Umeå, Stockholm, Sweden; 6 Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; 7 Department of Pediatrics, Astrid Lindgrens Barnsjukhus, Stockholm, Sweden; 8 Department of Pediatrics, University Hospital, Reykjavik, Iceland; 9 Department of Pediatrics, University Hospital, Trondheim, Norway; 10 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark; 11 Department of Pediatrics, University Hospital, Helsinki, Finland; and 12 Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Maintenance loses its innocence Michael A. Pulsipher Blood 2009 113: 6041-6042. [Full Text] [PDF] On the malignant potential of thiopurine therapy Nanne K. H. de Boer, Dirk P. van Asseldonk, and Adriaan A. van Bodegraven Blood 2009 113: 6258. [Full Text] [PDF] Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms? Kjeld Schmiegelow, Ibrahim Al-Modhawi, Mette Klarskov Andersen, Mikael Berendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, and Richard Weinshilboum, the Nordic Society for Paediatric Haematology and Oncology Blood 2009 113: 6258-6259. [Full Text] [PDF] This article has been cited by other articles: C.-H. Pui Toward a Total Cure for Acute Lymphoblastic Leukemia J. Clin. Oncol., November 1, 2009; 27(31): 5121 - 5123. [Full Text] [PDF] M. A. Pulsipher Maintenance loses its innocence Blood, June 11, 2009; 113(24): 6041 - 6042. [Full Text] [PDF] N. K. H. de Boer, D. P. van Asseldonk, and A. A. van Bodegraven On the malignant potential of thiopurine therapy Blood, June 11, 2009; 113(24): 6258 - 6258. [Full Text] [PDF] K. Schmiegelow, I. Al-Modhawi, M. K. Andersen, M. Berendtz, E. Forestier, H. Hasle, M. Heyman, J. Kristinsson, J. Nersting, R. Nygaard, et al. Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms? Blood, June 11, 2009; 113(24): 6258 - 6259. [Full Text] [PDF]

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